Complex I regulates mutant mitochondrial aldehyde dehydrogenase activity and voluntary ethanol consumption in rats

Abstract

Animals selectively bred for a desirable trait retain wanted genes but exclude genes that may counteract the expression of the former. The possible interactions between selected and excluded genes cannot be readily studied in transgenic or knockout animals but may be addressed by crossing animals bred for opposite traits and studying the F-2 offspring. Ninety-seven percent of Wistar-derived rats selectively bred for their voluntary low-alcohol consumption display a mutated nuclear allele of aldehyde dehydrogenase Aldh2(2) that encodes an enzyme with a low affinity for NAD(+), whereas rats bred for high-alcohol consumption do not present the Aldh2(2) allele. This enzyme is inserted into mitochondria, where NADH-ubiquinone oxidoreductase ( complex I) regenerates NAD(+). The possible influence of complex I on ALDH2 activity and voluntary ethanol intake was investigated. Homozygous Aldh2(2)/Aldh2(2) rats derived from a line of high-drinker F-0 females ( and low-drinker F-0 males) showed a markedly higher ethanol consumption (3.9 +/- 0.5 g . kg(-1) . day(-1)) than homozygous animals derived from a line of low-drinker F-0 females (and high-drinker F-0 males) (1.8 +/- 0.4 g . kg(-1) . day(-1)). Mitochondria of F-2 rats derived from high alcohol-consuming females were more active in oxidizing substrates that generate NADH for complex I than were mitochondria derived from low alcohol-consuming females, leading in the former to higher rates of acetaldehyde metabolism and to a reduced aversion to ethanol. This is the first demonstration that maternally derived genes can either allow or counteract the phenotypic expression of a mutated gene in the context of alcohol abuse or alcoholism.